Serum proteins in chronic hepatitis B patients treated with peginterferon alfa-2b

AIM: To study the differential protein profile in serum of hepatitis B patients.METHODS: Serum samples were obtained from patients with chronic hepatitis B who were receiving peginterferon alfa-2b.The serum samples were subjected to albumin depletion and analyzed by two-dimensional gel electrophoresis(2-DE).Differentially expressed protein spots were identified by electrospray ionizationquadrupole time-of-flight mass spectrometry.Alpha2-HS-glycoprotein,complement component C3c and CD5 antigen were further analyzed by an enzymelinked immunosorbent assay and immunonephelometry.RESULTS: Nineteen patients with HBeAg-positive chronic hepatitis B(CHB) were studied.These patients were followed for at least 1 year after treatment and were classified according to their treatment response: responders(n = 9) and non-responders(n = 10).2-DE and MS/MS analysis were performed to compare the serum proteins before initiating peginterferon alfa2b.From the quantitative analysis of the 2-D gel,7 proteins were detected between the two groups at different levels before treatment.Among these potential candidates,serum levels of alpha-2-HS-glycoprotein,complement component C3c and CD5 antigen-like precursor were further analyzed.In the validation phase,23 subjects,9 sustained responders and 14 nonresponders,were recruited.Interestingly,the levels of alpha-2-HS-glycoprotein and complement component C3c were elevated in the serum of the non-responders compared to the responders.CONCLUSION: Serum alpha-2-HS-glycoprotein and complement component C3c may be potential serum biomarkers in predicting the treatment response of peginterferon alfa-2b in patients with CHB prior to treatment.

Efficacy of low dose peginterferon alpha-2b with ribavirin on chronic hepatitis C

AIM: To assess the effi cacy of peginterferon alpha 2b at doses of 50 μg weekly and 80 μg weekly (based on body weight) plus ribavirin in HCV genotype 2 and genotype 3 chronic hepatitis C patients. METHODS: During the study period of Jan 2002 to Dec 2003, all patients diagnosed as chronic hepatitis C or HCV related compensated cirrhosis were treated with peginterferon alpha 2b 50 μg S/C weekly (body weight < 60 kg) or 80 μg S/C weekly (body weight > 60 kg) plus ribavirin 800 mg/d for 24 wk. RESULTS: Overall 28 patients, 14 patients in each group (based on body weight) were treated during the period. Out of 28 patients, 75% were genotype 3, 18% were genotype 2 and 7% were genotype 1. The mean dose of peginterferon alpha 2b was 0.91 μg/kg in group 1 and 1.23 μg/kg in group 2 respectively. The end of treatment and sustained virologic response rates were 82% and 78% respectively. Serious adverse effects were seen in 3.5% patients. CONCLUSION: Low dose peginterferon alpha 2b in combination with ribavirin for 24 wk is effective in HCV genotype 2 and 3 chronic hepatitis C patients.

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a

AIM: To examine the association between interferon(IFN) therapy and loss of hepatitis B surface antigen(HBs Ag) in inactive HBs Ag carriers. METHODS: This was a retrospective cohort study in inactive HBs Ag carriers, who were treatment-naive, with a serum HBs Ag level < 100 IU/m L and an undetectable hepatitis B virus(HBV) DNA level(< 100 IU/m L). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBs Ag, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS: Thirteen(65.0%) of 20 treated patients achieved HBs Ag loss, 12 of whom achieved HBs Ag seroconversion. Mean HBs Ag level in treated patients decreased to 6.69 ± 13.04 IU/m L after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/m L. Serum HBV DNA level remained undetectable(< 100 IU/m L) in all treated patients during the study. HBs Ag level of the control group decreased from 25.72 ± 25.58 IU/m L at baseline to 17.11 ± 21.62 IU/m L at week 96(P = 0.108). In the control group, no patient experienced HBs Ag loss/seroconversion, and two(5.0%) developed HBV reactivation.CONCLUSION: IFN treatment results in HBs Ag loss and seroconversion in a considerable proportion of inactive HBs Ag carriers with low HBs Ag concentrations.

重组人干扰素α-2b治疗慢性丙型肝炎不良反应分析

目的:评价重组人干扰素α-2b用于闽南沿海地区慢性丙型肝炎患者的安全性,为该地区患者用药提供参考资料。方法:采用回顾性分析方法,分析药品不良反应(Adverse drug reaction,ADR)总体发生率,男性、女性发生率;不同类型ADR发生构成比、ADR结果;ADR严重程度、干预情况。结果:ADR发生率为18.55%,其中男性ADR发生率为10.81%,女性ADR发生率为30.00%。ADR类型为骨髓抑制、其占比为71.43%;流感样症状、其占比为14.29%;甲状腺功能减退、斑丘疹、自身抗体异常,占比均为4.76%。ADR结果,骨髓抑制1例痊愈、2例好转、12例未好转;流感样症状3例均痊愈;甲状腺功能减退1例未好转;斑丘疹1例痊愈;自身抗体异常3例未好转。ADR严重程度占比,3级>1级>2级。3级ADR均进行药物干预,其中3例停药。2级ADR均进行药物干预。1级ADR,6例进行药物干预,3例未干预。结论:重组人干扰素α-2b用于闽南沿海地区丙型肝炎患者ADR发生率较高,3级较高,临床需加强指标的监测。

Pegylated interferon alfa-2b plus ribavirin for treatment of chronic hepatitis C

AIM: To study the safety and efficacy of pegylated interferon alfa-2b, indigenously developed in India, plus ribavirin in treatment of hepatitis C virus(HCV). METHODS: One-hundred HCV patients were enrolled in an open-label, multicenter trial. Patients were treated with pegylated interferon alfa-2b 1.5 μg/kg per week subcutaneously plus oral ribavirin 800 mg/d for patients with genotypes 2 and 3 for 24 wk. The same dose of peginterferon plus weight-based ribavirin(800 mg/d for ≤ 65 kg; 1000 mg/d for > 65-85 kg; 1200 mg/d for > 85-105 kg; 1400 mg/d for > 105 kg body weight) was administered for 48 wk for patients with genotypes 1 and 4. Serological and biochemical responses of patients were assessed.RESULTS: Eighty-two patients(35 in genotypes 1 and 4 and 47 in 2 and 3), completed the study. In genotype 1, 25.9% of patients achieved rapid virologic response(RVR): while the figures were 74.1% for early virologic response(EVR) and 44.4% for sustained virologic response(SVR). For genotypes 2 and 3, all patients bar one belonged to genotype 3, and of those, 71.4%, 87.5%, and 64.3% achieved RVR, EVR, and SVR, respectively. In genotype 4, 58.8%, 88.2%, and 52.9% of patients achieved RVR, EVR, and SVR, respectively. The majority of patients attained normal levels of alanine aminotransferase by 4-12 wk of therapy. Most patients showed a good tolerance for the treatment, although mild-to-moderate adverse events were exhibited; only two patients discontinued the study medication due to serious adverse events(SAEs). Eleven SAEs were observed in nine patients; however, only four SAEs were related to study medication.CONCLUSION: Peginterferon alfa-2b, which was developed in India, in combination with ribavirin, is a safe and effective drug in the treatment of HCV.

Add-on pegylated interferon augments hepatitis B surface antigen clearance vs continuous nucleos(t)ide analog monotherapy in Chinese patients with chronic hepatitis B and hepatitis B surface antigen≤1500 IU/mL:An observational study

BACKGROUND Nucleos(t)ide analog(NA)has shown limited effectiveness against hepatitis B surface antigen(HBsAg)clearance in chronic hepatitis B(CHB)patients.AIM To evaluate the efficacy and safety of add-on peginterferonα-2a(peg-IFNα-2a)to an ongoing NA regimen in CHB patients.METHODS In this observational study,195 CHB patients with HBsAg≤1500 IU/m L,hepatitis B e antigen(HBeAg)-negative(including HBeAg-negative patients or HBeAg-positive patients who achieved HBeAg-negative after antiviral treatment with NA)and hepatitis B virus-deoxyribonucleic acid<1.0×10^2 IU/mL after over 1 year of NA therapy were enrolled between November 2015 and December2018 at the Second Affiliated Hospital of Xi'an Jiaotong University,China.Patients were given the choice between receiving either peg-IFNα-2a add-on therapy to an ongoing NA regimen(add-on group,n=91)or continuous NA monotherapy(monotherapy group,n=104)after being informed of the benefits and risks of the peg-IFNα-2a therapy.Total therapy duration of peg-IFNα-2a was 48 wk.All patients were followed-up to week 72(24 wk after discontinuation of peg-IFNα-2a).The primary endpoint was the proportion of patients with HBsAg clearance at week 72.RESULTS Demographic and baseline characteristics were comparable between the two groups.Intention-to-treatment analysis showed that the HBsAg clearance rate in the add-on group and monotherapy group was 37.4%(34/91)and 1.9%(2/104)at week 72,respectively.The HBsAg seroconversion rate in the add-on group was 29.7%(27/91)at week 72,and no patient in the monotherapy group achieved HBsAg seroconversion at week 72.The HBsAg clearance and seroconversion rates in the add-on group were significantly higher than in the monotherapy group at week 72(P<0.001).Younger patients,lower baseline HBsAg concentration,lower HBsAg concentrations at weeks 12 and 24,greater HBsAg decline from baseline to weeks 12 and 24 and the alanine aminotransferase≥2×upper limit of normal during the first 12 wk of therapy were strong predictors of HBsAg clearance in patients with peg-IFNα-2a add-on treatment.Regarding the safety of the treatment,4.4%(4/91)of patients in the add-on group discontinued peg-IFNα-2a due to adverse events.No severe adverse events were noted.CONCLUSION Peg-IFNα-2a as an add-on therapy augments HBsAg clearance in HBeAg-negative CHB patients with HBsAg≤1500 IU/m L after over 1 year of NA therapy.

Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus

AIM: To describe our experience using a low-acceleratingdose regimen(LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus(HCV) recurrence. METHODS: From 2003, a protocolized LADR strategy was employed to treat liver transplant(LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28 B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B(rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include(1) patient and graft survival;(2) effect of anti-viral therapy on liver histology(fibrosis and inflammation);(3) incidence of on-treatment development of ACR, CDR, or PCH;(4) association of recipient and donor IL28 B genotype with SVR; and(5) incidence of antiviral therapy-associated adverse events(anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation.RESULTS: The overall SVR rate was 38%(29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt(P < 0.0001), donor age(P = 0.003), cytomegalovirus mismatch(P = 0.001), baseline serum bilirubin(P = 0.002), and baseline viral load(P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs(P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR(97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L(P = 0.01), total bilirubin ≥ 1.5 mg/d L(P = 0.001) and creatinine ≥ 2 mg/d L(P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the followup period. Treatment discontinuation and treatmentrelated mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six(25%) of the patients were deceased; among those who died, 25(54%) were due to liver-related complications, and 4 deaths(9%) occurred while receiving therapy(2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION: LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.

Sustained Responses in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue Drug-resistance after Peg-interferon Alfa-2a Add-on Treatment:A Long-term Cohort Study

Background and Aims:The use of additional nucleos(t)ide analogues(NAs)without cross-resistance to previously used NAs as a rescue therapy is recommended by most international guidelines for chronic hepatitis B patients with NAresistance.We aimed to investigate the efficacy and safety of combination therapy of peg-interferon(PegIFN)alfa-2a and NA in these patients,comparing to those who switch to an alternative NA therapy without cross-resistance.Methods:In this prospective,comparative and cohort study,data were collected from the patients'hospital records.Eligible patients were those with hepatitis B e antigen(HBeAg)positivity and resistance to one or more NAs.All patients were treated with alternative NA alone or in combination with PegIFN alfa-2a for 52 weeks or 72 weeks,respectively.HBeAg seroconversion was measured at the end of follow-up(EOF;more than 104 weeks after the end of treatment).Results:Sixty-three patients were recruited to the cohort study(NAtherapy group=31 patients;combination therapy group of NA and PegIFN alfa-2a=32 patients).At the EOF,significantly more patients in the combination therapy group(13/27,48.2%)achieved primary outcome of HBeAg seroconversion than those in the NA therapy group(4/32,12.5%)(p=0.003).Four patients(14.8%)in the combination therapy group achieved hepatitis B surface antigen(HBsAg)loss and HBsAg seroconversion,but none in the NA therapy group did(p=0.039).In the combination therapy group,16 patients(51.6%)achieved HBeAg seroconversion at the end of treatment,of which,11 patients(68.8%)maintained the response until EOF.Conclusions:Adding on PegIFN alfa-2a in combination with NA therapy might be an appropriate rescue treatment option for patients who have prior NA resistance.In addition,combination therapy induced sustained off-treatment biochemical responses in these patients.

Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients： A Randomized, Multicenter, Phase IIIb Open-Label Study （POTENT Study）

Background： Until now, various types of combined therapy with nucleotide analogs and pegylated interferon （Peg-INF） in patients with hepatitis B patients have been tried. Howe6ver, studies regarding the benefits of de novo combination, late-add on, and sequential treatmentare very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment. Methods： Between June 2010 and June 2015, hepatitis 13 e antigen （HBeAg）-positive patients （n = 162） received Peg-IFN for 48 weeks （mono-treatment group, n = 81） and entecavir （ETV） for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy （sequential treatment group, n = 81）. The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher＇s exact test, and regression analysis.Results： HBeAg seroconversion rate （18.2% vs. 18.2%, t = 0.03, P = 1.000） and seroclearance rate （19.7% vs. 19.7%, t = 0.03, P = 1.000） were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase （ALT） normalization （45.5% vs. 54.5%, t = 1.12, P = 0.296） and serum hepatitis B virus （HBV）-DNA 〈2000 U/L （28.8% vs. 28.8%, t = 0.10, P = 1.000） was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate （HBeAg seroconversion and serum HBV-DNA 〈2000 U/L） was not different in the two groups （12.1% vs. 16.7%, t = 1.83, P = 0.457）. Baseline HBV-DNA level （7 log10 U/ml vs. 7.5 log10 U/ml, t = 1.70, P = 0.019） and hepatitis B surface antigen titer （3.6 log10 U/ml vs. 4.0 log10 U/ml, t = 2.19, P = 0.020） were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively. Conclusions： The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens.